Dissertation/Thesis Abstract

Multivalent activation imparted by phosphate tethers: Metathesis efforts towards fostriecin
by McParland, James Paul, Ph.D., University of Kansas, 2009, 365; 3396468
Abstract (Summary)

The utilization and exploration of multifaceted phosphate tethers in synthesis is the focus of the dissertation research described herein. Desymmetrization of a readily derived psuedo-C2-symmetric monocyclic phosphate via highly diastereoselective anti-S N2' allylic displacement reactions are reported. This method utilizes a wide variety of zinc-derived organocuprates to afford E-1,2-syn -configured phosphate acid building blocks. Extension of this protocol to unsymmetric monocyclic phosphates exclusively yields 1,2-anti-configured products. Within this study stereoelectronic factors coupled with allylic strain ultimately govern regio- and diastereoselective cuprate reactions, thus further substantiating the Corey mechanism for organocuprate additions into allylic esters.

An approach towards fostriecin and fostriecin-like libraries utilizing rapid functionalization via a bicyclic phosphate methodology was investigated. This compact, multifaceted core coupled with an array of selective reactive pathways begged the synthetic queries enacted. Key to unraveling and expanding upon this central core of the molecule was realization of an exocyclic olefin oxidation and a diastereoselective Grignard addition where the source of Grignard used was found to play an important role. Selective cross-metathesis with subsequent attack of lithium thiophenol exploits the orthogonal leaving group ability of the phosphate to reveal the requisite stereo-tetrad of fostriecin. Not only does this sequence serve as a proof of concept approach for the total synthesis of fostriecin, it also serves as an archetype for the generation of fostriecin-like and phoslactomycin-like libraries.

The explorations of two synthetic approaches towards fostriecin from the bicyclic phosphate were embarked upon simultaneously. Intensive studies found the deactivating nature of the carboxylate oxygen on the alkene of lactone in conjunction with the lethargic protected tertiary allylic alcohol provided unacceptable conversion upon metathesis, despite installation of catalyst delivery vehicles. Attempts to utilize the unprotected bicyclic phosphate variant displayed preferential dimerization in the cross metathesis, while the relay primed analog was frustrated by competing elimination pathways. Analysis of an organometallic addition of the lactone core provided a viable route for future endeavors in the total synthesis.

Indexing (document details)
Advisor: Hanson, Paul R.
Commitee: Aube, Jeffrey, Malinakova, Helena C., Rubin, Michael, Tunge, Jon A.
School: University of Kansas
Department: Chemistry
School Location: United States -- Kansas
Source: DAI-B 71/03, Dissertation Abstracts International
Subjects: Organic chemistry
Keywords: Divalent activation, Fostriecin, Mulitvalent activation, Phosphate tethers, Relay cross-metathesis
Publication Number: 3396468
ISBN: 9781109641615
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